Epigenetic silencing of p21 by long non-coding RNA HOTAIR is involved in the cell cycle disorder induced by cigarette smoke extract
Epigenetic silencing of p21 by long non-coding RNA HOTAIR is involved in the cell cycle disorder induced by cigarette smoke extract
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DOI：
10.1016/j.toxlet.2015.10.016
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发表时间：
2016-01-05
影响因子：
3.5
通讯作者：
Liu, Qizhan
中科院分区：
文献类型：
--
作者：
Liu, Yi;Wang, Bairu;Liu, Qizhan
长链非编码RNA（lncRNA）是一种表观遗传调节因子，参与人类恶性肿瘤的发生。然而，人们对香烟烟雾诱导的lncRNA基因调控的分子机制知之甚少。我们最近发现，在人支气管上皮（HBE）细胞中，lncRNA，Hox转录反义基因间RNA（HOTAIR），与香烟烟雾提取物（CSE）引起的细胞周期的变化有关。在本研究中，我们报告了HOTAIR和增强子zeste同源物2（EZH 2）的表达增加，以及组蛋白H3（H3 K27 me 3）的Lys 27的三甲基化，影响细胞周期进程在CSE诱导的HBE细胞转化。通过siRNA抑制HOTAIR和EZH 2减弱了CSE诱导的p21水平降低。此外，ChIP测定证实需要HOTAIR和EZH 2来维持H3 K27 me 3与p21的启动子区域的相互作用; HOTAIR质粒和EZH 2 siRNA的组合使用支持这一观察结果。因此，HOTAIR通过EZH 2介导的H3 K27三甲基化对p21的表观遗传沉默有助于CSE诱导的细胞周期的变化。这些观察结果提供了对CSE诱导的肺癌发生的调节的进一步理解，并确定了新的治疗靶点。(C)2015爱思唯尔爱尔兰有限公司版权所有。
Long noncoding RNAs (lncRNAs), which are epigenetic regulators, are involved in human malignancies. Little is known, however, about the molecular mechanisms for lncRNA regulation of genes induced by cigarette smoke. We recently found that, in human bronchial epithelial (HBE) cells, the lncRNA, Hox transcript antisense intergenic RNA (HOTAIR), is associated with changes in the cell cycle caused by cigarette smoke extract (CSE). In the present study, we report that increased expression of HOTAIR and enhancer of zeste homolog 2 (EZH2), and tri-methylation of Lys 27 of histone H3 (H3K27me3), affect cell cycle progression during CSE-induced transformation of HBE cells. Inhibition of HOTAIR and EZH2 by siRNAs attenuated CSE-induced decreases of p21 levels. Further, ChIP assays verified that HOTAIR and EZH2 were needed to maintain the interaction of H3K27me3 with the promoter regions of p21; combined use of a HOTAIR plasmid and EZH2 siRNA supported this observation. Thus, HOTAIR epigenetic silencing of p21 via EZH2-mediated H3K27 trimethylation contributes to changes in the cell cycle induced by CSE. These observations provide further understanding of the regulation of CSE-induced lung carcinogenesis and identify new therapeutic targets. (C) 2015 Elsevier Ireland Ltd. All rights reserved.